Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

Inhibition of cardiac allograft arteriosclerosis by specific expression of NOS (eNOS or iNOS) in smooth muscle or endothelial cells

Lei, Jing (2008) Inhibition of cardiac allograft arteriosclerosis by specific expression of NOS (eNOS or iNOS) in smooth muscle or endothelial cells. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

Primary Text

Download (3MB) | Preview


Cardiac allograft arteriosclerosis (CAA) is the leading cause of death in cardiac transplantation recipients. Nitric oxide (NO) produced by NO donors or nitric oxide synthase (NOS) inhibits smooth muscle cell proliferation and migration, promotes endothelial cell proliferation, blocks endothelial cell apoptosis, prevents platelet and leukocyte adhesion and platelet aggregation. NO has been shown to inhibit intimal hyperplasia and suppress the development of cardiac allograft arteriosclerosis. Conversely, induction of NO in cardiomyocytes leads to myocardial apoptosis and suppresses cardiac function, mainly represented by decreased cardiac contractility. Based on these studies, we hypothesize that cell type-specific overexpression of eNOS or iNOS, in smooth muscle or endothelial cells, will inhibit the development of cardiac allograft arteriosclerosis without suppressing cardiac function. To test this hypothesis, we developed two gene delivery systems that specifically express NO in smooth muscle or endothelial cells. One system we constructed is adenoviral vectors that employed the fms-like tyrosine kinase-1 (Flt-1, -748 ~ +284 bp), or the intercellular molecule 2 (ICAM2, -292 ~ +44 bp) promoters to drive the human iNOS specific expression in endothelial cells. Another system we developed is vascular-specific iNOS inducible transgenic mice that employed the GeneSwitch system (Invitrogen) and vascular -specific promoter. We obtained two iNOS transgenic lines, in which iNOS can be induced by the ligand mifepristone with the supply of the Switch protein. To determine the efficacy of eNOS endothelial-specific expression on suppression of cardiac allograft arteriosclerosis, we employed eNOS transgenic mice in which the human eNOS promoter was driving the human eNOS expression. In a mouse heterotopic transplantation model, the male transgenic and female wild-type counterparts were used as donor and recipient, respectively. The donor grafts were harvested 60 days after transplantation and the percentage of vessel occlusion was determined. The vessel occlusion developed in the transegenic donor did not show significant difference compared to the wild-type control. As an alternative approach, the eNOS/GTPCH double transgenic mice will be used as donor and its efficacy will be determined. We hope that these proof-of -principle studies will serve as the basis for the development of an effective treatment strategy to prevent cardiac allograft arteriosclerosis.


Social Networking:
Share |


Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Lei, Jingjil19@pitt.eduJIL19
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairPitt, Brucebrucep@pitt.eduBRUCEP
Committee MemberDemetris, Anthohy Jdemetrisaj@upmc.eduDEMETRIS
Committee MemberBilliar, Timothy Rbilliartr@upmc.eduBILLIAR
Committee MemberDai,
Committee MemberVodovotz, Yoramvodovotzy@upmc.eduVODOVOTZ
Date: 11 April 2008
Date Type: Completion
Defense Date: 5 December 2007
Approval Date: 11 April 2008
Submission Date: 10 April 2008
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Cellular and Molecular Pathology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: cardiac allograft arteriosclerosis; endothelial cells-specific targeting; gene therapy; nitric oxide synthase; smooth muscle cell-specific targeting
Other ID:, etd-04102008-161216
Date Deposited: 10 Nov 2011 19:35
Last Modified: 19 Dec 2016 14:35


Monthly Views for the past 3 years

Plum Analytics

Actions (login required)

View Item View Item